BACKGROUND: Lung cancer is the most common neoplasm and the first cause-related mortality in developed and in most of non-developed countries. Epidemiological studies have demonstrated that even at low arsenic doses, the lungs are one of the main target organs and that chronic arsenic exposure has been associated with an increase in lung cancer development. Among the risk factors for cancer, arsenic methylation efficiency (As3MT) and the clearance of arsenic from cells by two members of the ATP-binding cassette (ABC) transporter family [multidrug resistance protein 1 (MRP1) and P-glycoprotein (P-gp)] play an important role in processing of arsenic and decreasing its intracellular levels. OBJECTIVE: Evaluate the association between chronic exposure to arsenic with polymorphism of three proteins involved in arsenic metabolism and efflux of the metalloid in subjects with lung cancer. RESULTS: The polymorphism of As3MT, MRP1 and P-gp modified the arsenic metabolism increasing significantly the As(V) urinary levels. A significant association between MRP1 polymorphisms with an increase in the risk for cancer was found. CONCLUSIONS: The high inorganic arsenic urinary levels registered in the studied subjects suggest a reduction in the efficiency of As3MT, MRP1 and P-gp firstly because of gene polymorphisms and secondarily because of high internal inorganic arsenic levels. MRP1 polymorphism was associated with two fold increase in the risk of lung cancer.